The program project consists of clinical and basic studies of factors influencing tolerance and dependence on opiates, CNS depressants, cannabinoids, cocaine, tobacco, opiate-like peptides and other drugs that may interact in clinical situations. Understanding mechanisms and effects in common between classes of drugs is a goal. Studies of the biochemical basis of tolerance and dependence continue with emphasis on hormones, cyclic nucleotides and calcium as regulators. Novel treatments of dependence emphasize non-narcotic treatment approaches and psychosocial interventions that change drug-seeking behavior. Scientific Component No. 2 studies naloxone-precipitated withdrawal following single doses of morphine in normal and opiate addict volunteers. How caffeine, dexamethasone and vasopressin modify the acquisition and expression of opiate dependence and psychological, physiological and neurochemical effects of morphine and beta-endorphin will be measured. Measurement techniques to follow acute dependence and correlates of protracted abstinence in former opiate addicts will be refined. Measures of morphine effects and precipitated withdrawal include symptom and mood changes, cardiovascular and electroencephalographic responses, including auditory evoked late potentials in auditory signal detection tasks and vigilance tasks. Plasma ACTH, cortisol, vasopressin and catecholamines will be measured to better compare animal and human models. Beta-endorphin will be compared to morphine. Disciplines involved include psychopharmacology, psychophysiology and clinical pharmacology. Information as to mechanisms, a practical new screening technique for opiate-like dependence liability, a sensitive index of protracted abstinence with treatment implications, and partial validation in humans of some animal models may come from these studies.